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The most prevalent psychoactive substances in cannabis are cannabinoids, including delta-9-tetrahydrocannabinol (Δ9-THC, commonly called simply THC). Some varieties, having undergone careful selection and growing techniques, can yield as much as 29% THC.[9] Another psychoactive cannabinoid present in Cannabis sativa is tetrahydrocannabivarin (THCV), but it is only found in small amounts and is in fact a cannabinoid antagonist.[10]

In addition, there are also similar compounds contained in cannabis that do not exhibit any psychoactive response but are obligatory for functionality: cannabidiol (CBD), an isomer of THC; cannabinol (CBN), an oxidation product of THC; cannabivarin (CBV), an analog of CBN with a different sidechain, cannabidivarin (CBDV), an analog of CBD with a different side chain, and cannabinolic acid. How these other compounds interact with THC is not fully understood. Some clinical studies have proposed that CBD acts as a balancing force to regulate the strength of the psychoactive agent THC. Marijuana with relatively high ratios of CBD:THC is less likely to induce anxiety than marijuana with low CBD:THC ratios.[11] CBD is also believed to regulate the body’s metabolism of THC by inactivating cytochrome P450, an important class of enzymes that metabolize drugs. Experiments in which mice were treated with CBD followed by THC showed that CBD treatment was associated with a substantial increase in brain concentrations of THC and its major metabolites, most likely because it decreased the rate of clearance of THC from the body.[11] Cannabis cofactor compounds have also been linked to lowering body temperature, modulating immune functioning, and cell protection. The essential oil of cannabis contains many fragrant terpenoids which may synergize with the cannabinoids to produce their unique effects. THC is converted rapidly to 11-hydroxy-THC, which is also pharmacologically active, so the drug effect outlasts measurable THC levels in blood.[9]

The CB1 receptor is found primarily in the brain and mediates the psychological effects of THC. The CB2 receptor is most abundantly found on cells of the immune system. Cannabinoids act as immunomodulators at CB2 receptors, meaning they increase some immune responses and decrease others. For example, nonpsychotropic cannabinoids can be used as a very effective anti-inflammatory.[11] The affinity of cannabinoids to bind to either receptor is about the same, with only a slight increase observed with the plant-derived compound CBD binding to CB2 receptors more frequently. Cannabinoids likely have a role in the brain’s control of movement and memory, as well as natural pain modulation. It is clear that cannabinoids can affect pain transmission and, specifically, that cannabinoids interact with the brain's endogenous opioid system and may affect dopamine transmission.[13] This is an important physiological pathway for the medical treatment of pain.

The cannabinoid receptor is a typical member of the largest known family of receptors called a G protein-coupled receptor. A signature of this type of receptor is the distinct pattern of how the receptor molecule spans the cell membrane seven times. The location of cannabinoid receptors exists on the cell membrane, and both outside (extracellularly) and inside (intracellularly) the cell membrane. CB1 receptors, the bigger of the two, are extraordinarily abundant in the brain: 10 times more plentiful than μ-opioid receptors, the receptors responsible for the effects of morphine. CB2 receptors are structurally different (the sequence similarity between the two subtypes of receptors is 44%), found only on cells of the immune system, and seems to function similarly to its CB1 counterpart. CB2 receptors are most commonly prevalent on B-cells, natural killer cells, and monocytes, but can also be found on polymorphonuclear neutrophil cells, T8 cells, and T4 cells. In the tonsils the CB2 receptors appear to be restricted to B-lymphocyte-enriched areas.

Most cannabinoids are lipophilic (fat soluble) compounds that easily store in fat, thus yielding a long elimination half-life relative to other recreational drugs. The THC molecule, and related compounds, are usually detectable in drug tests from 3 days up to 10 days according to Redwood Laboratories, heavy users can produce positive tests for up to 3 months after ceasing cannabis use (see drug test).

THC has an extremely low toxicity and the amount that can enter the body through the consumption of cannabis plants poses no threat of death. In lab animal tests, scientists have had much difficulty administering a dosage of THC that is high enough to be lethal.[citation needed] Accordingly, there is little reason to believe a human would self-administer such doses. Indeed, a 1988 ruling from the United States Department of Justice concluded that "In practical terms, marijuana cannot induce a lethal response as a result of drug-related toxicity."[14]

According to the Merck Index,[15] the Template:LD50 of THC (the dose which causes the death of 50% of individuals) is 1270 mg/kg for male rats and 730 mg/kg for female rats from oral consumption in sesame oil, and 42 mg/kg for rats from inhalation.[16]

The ratio of cannabis material required to produce a fatal overdose to the amount required to saturate cannabinoid receptors and cause intoxication is approximately 40,000:1.[17][18] It is extremely difficult to overdose by smoking marijuana; a typical marijuana "joint" contains less than 10 mg of THC, and one would have to smoke thousands of those in a short period of time to approach toxic levels. According to a 2006 United Kingdom government report, using cannabis is much less dangerous than tobacco, prescription drugs, and alcohol in social harms, physical harm, and addiction.[19] It was found in 2007 that while tobacco and cannabis smoke are quite similar, cannabis smoke contained higher amounts of ammonia, hydrogen cyanide, and nitrogen oxides, but lower levels of carcinogenic polycyclic aromatic hydrocarbons (PAHs).[20] This study found that directly inhaled cannabis smoke contained as much as 20 times as much ammonia and 5 times as much hydrogen cyanide as tobacco smoke and compared the properties of both mainstream and sidestream (smoke emitted from a smouldering 'joint' or 'cone') smoke.[20] Mainstream cannabis smoke was found to contain higher concentrations of selected polycyclic aromatic hydrocarbons (PAHs) than sidestream tobacco smoke.[20] However, other studies have found much lower disparities in ammonia and hydrogen cyanide between cannabis and tobacco, and that some other constituents (such as polonium-210, lead, arsenic, nicotine, and tobacco-specific nitrosamines) are either lower or non-existent in cannabis smoke.[21][22]

When smoked, the short-term effects of cannabis manifest within seconds and are fully apparent within a few minutes,[23] typically lasting for 2–3 hours.[24] The duration of noticeable effects has been observed to diminish due to prolonged, repeated use and the development of a tolerance to cannabinoids.

The psychoactive effects of cannabis, known as a "high", are subjective and can vary based on the individual and the method of use.

Cannabis is often considered an atypical, unique and sometimes paradoxical psychotropic due to its vast and sometimes contradictory array of effects. The subjective experience induced by imbibing in cannabis use can be considered stimulatory and yet also sedative or depressant, while also having markedly mild psychedelic and even dissociative characteristics.

Cannabis also produces many subjective and highly tangible effects, such as greater enjoyment of food taste and aroma (The Munchies), an enhanced enjoyment of music and comedy, and marked distortions in the perception of time and space (where experiencing a "rush" of ideas from the bank of long-term memory can create the subjective impression of long elapsed time, while a clock reveals that only a short time has passed). At higher doses, effects can include altered body image, auditory and/or visual illusions, pseudo-hallucinatory or (rarely, at very high doses) fully hallucinatory experiences, and ataxia from selective impairment of polysynaptic reflexes. In some cases, cannabis can lead to dissociative states such as depersonalization[27][28] and derealization;[29] such effects are most often considered desirable, but have the potential to induce panic attack and paranoia in some unaccustomed users.

The total short-term duration of cannabis use when smoked is based on the potency and how much is smoked. Effects can typically last two to three hours.[24]

A study of ten healthy, robust, male volunteers who resided in a residential research facility sought to examine both acute and residual subjective, physiologic, and performance effects of smoking marijuana cigarettes. On three separate days, subjects smoked one NIDA marijuana cigarette containing either 0%, 1.8%, or 3.6% THC, documenting subjective, physiologic, and performance measures prior to smoking, five times following smoking on that day, and three times on the following morning. Subjects reported robust subjective effects following both active doses of marijuana, which returned to baseline levels within 3.5 hours. Heart rate increased and the pupillary light reflex decreased following active dose administration with return to baseline on that day. Additionally, marijuana smoking acutely produced decrements in smooth pursuit eye tracking. Although robust acute effects of marijuana were found on subjective and physiological measures, no effects were evident the day following administration, indicating that the residual effects of smoking a single marijuana cigarette are minimal.[32]

A Dutch double blind, randomized, placebo-controlled, cross-over study examining male volunteers aged 18–45 years with a self-reported history of regular cannabis use concluded that smoking of cannabis with very high THC levels (marijuana with 9–23% THC), as currently sold in coffee shops in the Netherlands, may lead to higher THC blood-serum concentrations. This is reflected by an increase of the occurrence of impaired psychomotor skills, particularly among younger or inexperienced cannabis smokers, who do not always adapt their smoking-style to the higher THC content.[33] High THC concentrations in cannabis were associated with a dose-related increase of physical effects (such as increase of heart rate, and decrease of blood pressure) and psychomotor effects (such as reacting more slowly, being less concentrated, making more mistakes during performance testing, having less motor control, and experiencing drowsiness). It was also observed during the study that the effects from a single joint lasted for more than eight hours. Reaction times remained impaired five hours after smoking, when the THC serum concentrations were significantly reduced, but still present. However, it is important to note that the subjects (without knowing the potency) were told to finish their (unshared) joints rather than titrate their doses, leading in many cases to significantly higher doses than they would normally take. Also, when subjects smoke on several occasions per day, accumulation of THC in blood-serum may occur.

When taken orally, the psychoactive effects take longer to manifest and generally last longer, typically lasting for 4–10 hours after consumption.[34] Very high doses may last even longer. Also, oral use eliminates the need to inhale toxic combustion products created by smoking, which eliminates much of the respiratory and cardiovascular harm associated with cannabis smoking.

Most notably, the two areas of motor control and memory are where the effects of cannabis are directly and irrefutably evident. Cannabinoids, depending on the dose, inhibit the transmission of neural signals through the basal ganglia and cerebellum. At lower doses, cannabinoids seem to stimulate locomotion while greater doses inhibit it, most commonly manifested by lack of steadiness (body sway and hand steadiness) in motor tasks that require a lot of attention. Other brain regions, like the cortex, the cerebellum, and the neural pathway from cortex to striatum, are also involved in the control of movement and contain abundant cannabinoid receptors, indicating their possible involvement as well.

Experiments on animal and human tissue have demonstrated a disruption of short-term memory formation,[11] which is consistent with the abundance of CB1 receptors on the hippocampus, the region of the brain most closely associated with memory. Cannabinoids inhibit the release of several neurotransmitters in the hippocampus, like acetylcholine, norepinephrine, and glutamate, resulting in a major decrease in neuronal activity in that region. This decrease in activity resembles a "temporary hippocampal lesion."[11] In the end, this procedure could lead to the blocking of cellular processes that are associated with memory formation.

In in-vitro experiments THC at extremely high concentrations, which could not be reached with commonly consumed doses, caused competitive inhibition of the AChE enzyme and inhibition of β-amyloid peptide aggregation, the cause of Alzheimer's disease. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of A aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.[36]

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A 2001 study by the United Kingdom Transit Research Laboratory (TRL) specifically focuses on the effects of cannabis use on driving,[37] and is one of the most recent and commonly quoted studies on the subject. The report summarizes current knowledge about the effects of cannabis on driving and accident risk based on a review of available literature published since 1994 and the effects of cannabis on laboratory based tasks.

The study identified young males, amongst whom cannabis consumption is frequent and increasing, and in whom alcohol consumption is also common, as a risk group for traffic accidents. This is due to driving inexperience and factors associated with youth relating to risk taking, delinquency and motivation. These demographic and psychosocial variables may relate to both drug use and accident risk, thereby presenting an artificial relationship between use of drugs and accident involvement.

The effects of cannabis on laboratory-based tasks show clear impairment with respect to tracking ability, attention, and other tasks depending on the dose administered. Both simulation and road trials generally find that driving behavior shortly after consumption of larger doses of cannabis results in:

increased variability in lane position (such as taking a curve too tightly or too loosely).

longer decision times, leading to slower responses to driving situations

Kelly, Darke and Ross[38] show similar results, with laboratory studies examining the effects of cannabis on skills utilised while driving showing impairments in tracking, attention, reaction time, short-term memory, hand-eye coordination, vigilance, time and distance perception, and decision making and concentration. An EMCDDA[39] review concluded that "the acute effect of moderate or higher doses of cannabis impairs the skills related to safe driving and injury risk", specifically "attention, tracking and psychomotor skills".[39]
In their review of driving simulator studies, Kelly et al.[38] conclude that there is evidence of dose-dependent impairments in cannabis-affected drivers' ability to control a vehicle in the areas of steering, headway control, speed variability, car following, reaction time and lane positioning. The researchers note that "even in those who learn to compensate for a drug's impairing effects, substantial impairment in performance can still be observed under conditions of general task performance (i.e. when no contingencies are present to maintain compensated performance)."[39]

Cannabis arteritis is a very rare peripheral vascular disease similar to Buerger's disease. There were about 50 confirmed cases from 1960 to 2008, all of which occurred in Europe.[40] However, all of the cases also involved tobacco (a known cause of Buerger's disease) in one way or another, and nearly all of the cannabis use was quite heavy. In Europe, cannabis is typically mixed with tobacco, in contrast to North America.

A 2008 study by the National Institutes of Health Biomedical Research Centre in Baltimore found that heavy, chronic smoking of marijuana (138 joints per week) changed blood proteins associated with heart disease and stroke.[41] This is a result of raised carboxyhemoglobin levels from carbon monoxide. A similar increase in heart disease and ischemic strokes is observed in tobacco smokers, which suggests that the harmful effects come from combustion products, not marijuana.

Contaminants may be found in hashish obtained from "soap bar"-type sources.[44] The dried flowers of the plant may be contaminated by the plant taking up heavy metals and other toxins from its growing environment,[45] or by the addition of lead or glass beads, used to increase the weight or to make the cannabis appear as if it has more crystal-looking trichomes indicating a higher THC content.[46] Users who burn hot or mix cannabis with tobacco are at risk of failing to detect deviations from appropriate cannabis taste.

Despite cannabis being generally perceived as a natural or "chemical-free" product,[47] in a recent Australian survey[48] one in four Australians consider cannabis grown indoors under hydroponic conditions to be a greater health risk due to increased contamination, added to the plant during cultivation to enhance the plant growth and quality.

The most obvious confounding factor in cannabis research is the prevalent usage of other recreational drugs, especially alcohol and nicotine.[49] Such complications demonstrate the need for studies on cannabis that have stronger controls, and investigations into alleged symptoms of cannabis use that may also be caused by tobacco. Some critics question whether agencies doing the research make an honest effort to present an accurate, unbiased summary of the evidence, or whether they "cherry-pick" their data to please funding sources which may include the tobacco industry or governments dependent on cigarette tax revenue; others caution that the raw data, and not the final conclusions, are what should be examined.[50]

Cannabis also has been shown to have a synergistic cytotoxic effect on lung cancer cell cultures in vitro with the food additive butylated hydroxyanisole (BHA) and possibly the related compound butylated hydroxytoluene (BHT). The study concluded, "Exposure to marijuana smoke in conjunction with BHA, a common food additive, may promote deleterious health effects in the lung." BHA & BHT are human-made fat preservatives, and are found in many packaged foods including: plastics in boxed cereal, Jello, Slim Jims, and more.[51]Template:Elucidate

The Australian National Household Survey of 2001[52] showed that cannabis use in Australia is rarely used without other drugs. 95% of cannabis users also drank alcohol; 26% took amphetamines; 19% took ecstasy and only 2.7% reported not having used any other drug with cannabis.[53] While research has been undertaken on the combined effects of alcohol and cannabis on performing certain tasks, little research has been conducted on the reasons why this combination is so popular. Evidence from a controlled experimental study undertaken by Lukas and Orozco[54] suggests that alcohol causes THC to be absorbed more rapidly into the blood plasma of the user. Data from the Australian National Survey of Mental Health and Wellbeing[55] found that three-quarters of recent cannabis users reported using alcohol when cannabis was not available.[56]

Studies on cannabis and memory are hindered by small sample sizes, confounding drug use, and other factors.[4] The strongest evidence regarding cannabis and memory focuses on its short-term negative effects on short-term and working memory.[4]

A 2008 review of the evidence surrounding the acute impact on memory concluded that cannabinoids impair all aspects of short-term memory, especially short-term episodic and working memory.[2] One small study found that no learning occurred during the 2 hour period in which the subjects (infrequent users) were "stoned".[57]

The feeling of increased appetite following the use of cannabis has been documented for hundreds of years,[58] and is commonly known as "the munchies" in popular culture. Clinical studies and survey data have found that cannabis increases food enjoyment and interest in food.[59][60] Scientists have claimed to be able to explain what causes the increase in appetite, concluding that "endocannabinoids in the hypothalamus activate cannabinoid receptors that are responsible for maintaining food intake".[60]
Endogenous cannabinoids have recently been discovered in foods such as chocolate and bovine milk.[61][62]

It is widely accepted that the neonatal survival of many species "is largely dependent upon their suckling behavior, or appetite for breast milk"[63] and recent research has identified the endogenous cannabinoid system to be the first neural system to display complete control over milk ingestion and neonatal survival.[64] It is possible that "cannabinoid receptors in our body interact with the cannabinoids in milk to stimulate a suckling response in newborns so as to prevent growth failure".[63]

Though the long-term effects of cannabis have been studied, there remains much to be concluded; debated topics include the drug's addictiveness, its potential as a "gateway drug", its effects on intelligence and memory, and its contributions to mental disorders such as schizophrenia and depression. On some such topics, such as the drug's effects on the lungs, relatively little research has been conducted, leading to division as to the severity of its impact.

More research is no guarantee of greater consensus in the field of cannabis studies, however; both advocates and opponents of the drug are able to call upon multiple scientific studies supporting their respective positions. Cannabis has been correlated with the development of various mental disorders in multiple studies, for example a recent 10 year study on 1923 individuals from the general population in Germany, aged 14–24, concluded that cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder.[68]

Other studiesTemplate:Which? differ widely as to whether cannabis use is the cause of the mental problems, whether the mental problems encourage cannabis use, or whether both the cannabis use and the mental problems are the effects of some other cause. Still other studies even encourage the use of cannabis in treating schizophrenia. Similarly, efforts to prove the "gateway drug" hypothesis that cannabis and alcohol makes users more inclined to become addicted to "harder" drugs like cocaine and heroin have produced mixed results, with different studies finding varying degrees of correlation between the use of cannabis and other drugs, and some finding none. Some, however, believe the "gateway effect," currently being pinned on the use of marijuana, should not be attributed to the drug itself but rather the illegality of the drug in most countries. Supporters of this theory believe that the grouping of marijuana and harder drugs in law is, in fact, the cause of users of marijuana to move on to those harder drugs.

Most microorganisms found in cannabis only affect plants and not humans, but some microorganisms, especially those that proliferate when the herb is not correctly dried and stored, can be harmful to humans. Some users may store marijuana in an airtight bag or jar in a refrigerator to prevent fungi and bacterial growth.[69]

Mold is also found in smoke from mold infected cannabis,[69][70] and the lungs and nasal passages are a major means of contracting fungal infections. Levitz and Diamond (1991) suggested baking marijuana in home ovens at 150 °C [302 °F], for five minutes before smoking. Oven treatment killed conidia of A. fumigatus, A. flavus and A. niger, and did not degrade the active component of marijuana, tetrahydrocannabinol (THC)."[69]

In many countries, experimental science regarding cannabis is restricted due to its illegality. Thus, cannabis as a drug is often hard to fit into the structural confines of medical research because appropriate, research-grade samples are difficult to obtain for research purposes, unless granted under authority of national governments.

The cannabis that is available for research studies in the United States is grown at the University of Mississippi and solely controlled by the NIDA, which has veto power over the Food and Drug Administration (FDA) to define accepted protocols. Since 1942, when cannabis was removed from the U.S. Pharmacopoeia and its medical use was prohibited, there have been no legal (under federal law) privately funded cannabis production projects. This has resulted in a limited amount of research being done and possibly in NIDA producing cannabis which has been alleged to be of very low potency and inferior quality.[72]

In countries such as the United Kingdom a license for growing cannabis is required if it is to be used for botanical or scientific reasons. It is referred to as a "controlled drug". In such countries a greater depth and variety of scientific research has been performed. Recently several habitual smokers were invited to partake in various tests by British medical companies in order for the UK government to ascertain the influence of cannabis on operating a motor vehicle, with the conclusion that marijuana strongly impairs the ability to drive a motor vehicle. [citation needed] A different UK study confirmed that while motor reflexes can be impaired by cannabis, the resulting impairment is far less of a threat than the motor impairment brought on through alcohol intake. [citation needed] The Transport Research Library of Berkshire concluded that in most cases, cannabis intake made subjects drive slower on the road.

↑ (2005). Cannabinoid Action Depends on Phosphorylation of Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa at the Protein Kinase A Site in Striatal Projection Neurons. Journal of Neuroscience25 (37): 8432–8.

↑Public opinion on drugs and drug policy. Transform Drug Policy Foundation: Fact Research Guide. "Data is notoriously easy to cherry pick or spin to support a particular agenda or position. Often the raw data will conceal all sorts of interesting facts that the headlines have missed." Transform Drug Policy Foundation, Easton Business Centre, Felix Rd., Bristol, UK. Retrieved on 24 March 2007.